Despite major advances in the prevention and treatment of cardiovascular diseases, as is evident from the substantial decline in mortality due to acute myocardial infarction and strokes in the United States and in most European countries, national statistics indicate that the incidents and prevalence of congestive heart failure (CHF) have been increasing in recent years. Patients with CHF have an impaired quality of life and a shortened life expectation. CHF is defined generally as the inability of the heart to deliver enough blood to the peripheral tissues to meet metabolic demands. Although angiotensin-converting enzymes (ACE) inhibitors have been shown to modify the natural course of CHF reducing the mortality rate by 30%, the underlying disease continues to evolve, becoming progressively unresponsive to common drugs, until eventually intravenous inotropic support is needed. At end-stage, heart transplantation becomes the only therapeutic option.
It has been suggested that heart failure progresses as a result of the over-expression of biologically active molecules that are capable of exerting toxic effects on the heart and circulation (Bristow, 1984; Tan et al, 1991; Dunn 2003). Furthermore, several studies have demonstrated that congestive heart failure (CHF) patients are characterized by persistent immune activation (Damas et al., 2001). In fact, many aspects of the syndrome of heart failure, for example, left ventricular dysfunction, pulmonary edema, cardiomyopathy, endothelial dysfunction, anorexia and cachexia, can be caused by the biological effects of pro-inflammatory cytokines resulting from persistent activation of surrounding cells. Secondly, the pattern of expression of pro-inflammatory mediators is very similar to that observed with the classical neurohormones such as angiotensin II and norepinephrine that are believed to play an important role in the progression of heart failure (Mann, 1999). Together, these findings support the rationale for targeting inflammatory mediators, or cytokines, in heart failure.
Inflammation is often induced by pro-inflammatory cytokines, such as tumor necrosis factor (TNF), interleukin (IL)-1α, IL-1β, IL-6, IL-8, IL-18, interferonγ, platelet activating factor (PAF), macrophage migration inhibitory factor (MIP), and other compounds (Thompson, 1998—book). These factors are produced by a variety of different cell types, most importantly immune cells but also non-immune cells such as smooth muscle cells and neurons (Yeh & Schuster, 1999). Pro-inflammatory cytokines contribute to a variety of diseases through their release which often results in an inflammatory cascade of both cellular and systemic events. Mammals respond to and regulate inflammatory cascades in part through nervous system regulation, (Besedovsky et al., 1986; Gaykema et al., 1995; Fleshner et al., 1998; Watkins and Maier, 1999)
Pro-inflammatory cytokines such as TNFα and IL-1β modulate cardiovascular functions by a variety of mechanisms. For example, cytokines can depress myocardial contractility (Yokokyam et al., 1993; Gulick et al., 1989; Finkel et al., 1992), induce cardiomyocyte hypertrophy and iterstitial fibrosis (Yokoyama et al., 1997; Hirota et al., 1999) and promote cardiomyocyte apoptosis and collagen production (Krown et al. 1996; Pulkki, 1997; Li et al., 2000). Interestingly, TNF, IL-1β, and IL-6 are expressed in direct relation to worsening New York Heart Association (NYHA) functional classification (Diwan et al., 2003). In addition, there is increasing evidence that many of the conventional therapies for heart failure may work, at least in part, through the modulation of pro-inflammatory cytokines. For example, administration of angiotensin type-1 receptor antagonists and/or β1-selective adrenergic antagonists lead to decreases in circulating levels of inflammatory mediators in patients with heart failure.
Traditional therapies for treating heart failure include the administration of ACE inhibitors and/or vasodilators. More recently, agents designed to reduce inflammation, for example, enfliximab—Remicade, etanercept—Enbrel, pentoxifylline, intravenous immunoglobulin, have been used in combination with the traditional therapies with mixed results.
Therapies aimed solely at reducing the pro-inflammatory mediator TNF, e.g., enfliximab—Remicade and etanercept—Enbrel, have resulted in negative clinical trials. Two large pivotal trials were halted early due to a lack of improvement with treatment (RECOVER and RENAISSANCE for etanercept). A third study investigating the use of enfliximab was stopped due to an increased incidence of mortality and hospitalization for worsening CHF. Although successful in the treatment of rheumatoid arthritis and Crohn's, these agents are known to be intrinsically toxic to the heart. Additionally, their mechanism of action is not sufficient to reduce cardiac inflammation.
While the rationale for targeting the pro-inflammatory cascade in heart failure is well established, current therapies have failed to target pro-inflammatory mediators with agents that can be safely used in the context of heart failure. Additionally, these failed attempts suggest that targeting a single component (ie cytokine) of the inflammatory cascade may not be sufficient in a disease as complex as heart failure. Instead, an approach that harnesses more higher order functions, such as the nervous system's ability to regulate inflammatory functions, may be more effective in modulating the entire inflammatory cascade.
Recently it has been shown that electrical stimulation of the vagus nerve is capable of ameliorating immune activation (Borovikova et al., 2000; Guarini et al., 2003) and is therefore useful in inhibiting inflammatory cytokine cascades that mediate several disease conditions. This discovery is based on the finding that treatment of a pro-inflammatory cytokine producing cell with a cholinergic agonist attenuates the release of pro-inflammatory cytokines from that cell (Borovikova et al., 2000a—Nature and Boroviokova et al., 2000b—Auton Neurosci). Subsequent findings demonstrated that electrical stimulation of the vagus nerve fibers causes the release of acetylcholine which acts on the pro-inflammatory cytokine producing cells in-vivo to attenuate an inflammatory response. Stimulation of the vagus nerve is capable of reducing the exacerbated pro-inflammatory immune response induced by endotoxin or hemorrhagic shock. The significant body of evidence demonstrating sustained expression of pro-inflammatory cytokines produces detrimental effects in the heart suggests that vagal nerve stimulation may ameliorate these effects. In addition, cardiac vagal activity is diminished in chronic heart failure.
Vagal nerve stimulation increases vagal tone, which produces antiarrhythmic effects and vasodilation. Depending on the chosen location of stimulation, vagal stimulation may exert beneficial effects in CHF in addition to modulating the pro-inflammatory response. For example, vagal stimulation increases the density of cardiac noradrenergic plexuses, increase cardiac blood supply and improve ventricular contractility (Zamotrinsky, 2001). In the present invention, stimulation of the vagus to modulate the inflammatory response during pacing of the heart may also operate through other pathways to restore autonomic balance.
A number of proposals have been proposed to target specific cytokines and/or the entire inflammatory cascade to treat congestive heart failure through biologics and pharmaceutical means as described in detail in U.S. Pat. Nos. 6,537,540, 5,998,386, 6,221,851, 6,572,895, 5,977,408 and 6,589,954 all incorporated herein by reference. The medical literature also discloses treatment strategies to inhibit pro-inflammatory cytokines (Diwan et al., 2003; MacGowan and McNamara, 2002; Damas et al., 2001; Greenberg et al., 2001; Francis, 1998), all incorporated herein by reference. These approaches have focused predominately on inhibiting single cytokines rather than targeting the broad inflammatory cascade of events. The negative clinical trials demonstrate that the past treatment strategies aimed at inhibiting pro-inflammatory cytokines did not demonstrate clinical benefit for patients with CHF. It appears that an effective immuno-modulation strategy in the heart must target pre-translational (intracellular) TNF rather than soluble/cell surface TNF, as well as the more broad inflammatory cascade.
Vagus nerve stimulation (VNS) targets pro-inflammatory agents at the requisite point in their exacerbation, making VNS a useful strategy to resist cardiac inflammation. For example, PCT patent application no. WO 01/89526, incorporated herein by reference, discloses a method of electrically stimulating the efferent vagal nerve to inhibit the pro-inflammatory cytokine cascade to treat congestive heart failure.
Stimulation of the vagus nerve has been proposed to control various heart rate functions in patients suffering from heart failure. For example, U.S. Pat. No. 6,473,644 discloses stimulating the vagus nerve to modulate heart rate and U.S. Pat. No. 5,203,326 discloses an anti-arrhythmia pacemaker wherein electrical stimulation is delivered to a patient's vagal cervical ganglion, both incorporated herein by reference.
In the normal human heart, the sino-atrial (SA) node, generally located near the junction of the superior vena cava and the right atrium, constitutes the primary natural pacemaker initiating rhythmic electrical excitation. The cardiac impulse arising from the SA node is transmitted through the atrial conduction pathways of Bachmann's bundle and internodal tracts at the atrial level, thereby causing the two atrial chambers to contract. The contraction of the atrial chambers pumps blood from those chambers into the respective ventricular chambers. The excitation impulse is further transmitted to the ventricles through the atrio-ventricular (AV) node, and via a conduction system comprising the Bundle of His, or Common Bundle, the right and left bundle branches, and the Purkinje fibers. In response, the ventricles contract, the right ventricle pumping unoxygenated blood through the pulmonary artery to the lungs and the left ventricle pumping oxygenated blood through the aorta and arterial tree throughout the body. Disruption of this natural pacing and conduction system as a result of aging or disease is often successfully treated by artificial cardiac pacing using an implantable pulse generator, from which rhythmic electrical pulses are applied to the heart at a desired rate. One or more heart chambers may be electrically paced depending on the location and severity of the conduction disorder, see U.S. Patent Publication No. 2001/0049543, incorporated herein by reference.
A common type of intra-atrial conduction defect is known as intra-atrial block (IAB), a condition where the atrial activation is delayed in getting from the right atrium (RA) to the left atrium (LA). In left bundle branch block (LBBB) and right bundle branch block (RBBB), the activation signals are not conducted in a normal fashion along the right or left bundle branches respectively. Thus, in a patient with bundle branch block, the activation of the ventricle is slowed, and the QRS is seen to widen due to the increased time for the activation to traverse the conduction path.
In patients suffering from CHF, the right and left heart chambers may not contract in synchrony with each other. In such cases, cardiac output deteriorates because the contractions of the right and left heart chambers are not synchronized sufficiently to pump blood. It is believed that cardiac output can be significantly improved when left and right chamber synchrony is restored. In fact, clinical investigation performed on patients who suffer from heart failure (i.e., inability of the heart to pump the required amount of blood) indicates that for a certain subset of these patients simultaneous stimulation of the left and right ventricles may be advantageous.
In the cardiac cycle, a P wave of a patient's electrocardiogram (ECG) is produced by a depolarization of the atrial fibers just before they contract, and, when the cardiac impulse reaches the ventricular fibers to stimulate them into depolarization, a QRS complex is produced just before contraction of the ventricular walls. This is followed by a T wave which is indicative of the electrical activity occurring upon repolarization of the ventricular fibers. Simultaneous stimulation of the left and right ventricles can be beneficial therapy to patients whose ECG displays a marked desynchronization in contraction of the two ventricular chambers. In such cases, it is observed that after a right ventricular stimulation, considerable time may elapse for the cardiac impulse to travel from the apex of the right ventricle through the septum and to the free wall of the left ventricle, with the septum contracting earlier than the latter. Consequently, the mechanical forces of the ventricular contraction are less favorable for an effective hemodynamic output in such patients. The duration or width of the QRS complex may increase because of an injury to the Purkinje fibers that in habit and stimulate the ventricular septum and the lateral ventricular walls, and which could therefore increase the time for the impulse to spread throughout the ventricular walls. Patients who display a lack of ventricular synchronization primarily exhibit a wide QRS complex indicative of a bundle branch block—generally a LBBB.
A number of proposals have been proposed for providing pacing therapies to restore synchronous depolarization and contraction of a single heart chamber or right and left, upper and lower, heart chambers as described in detail in U.S. Pat. Nos. 5,403,356, 5,797,970, 5,902,324, 5,720,768 and 5,792,203 all incorporated herein by reference. The proposals appearing in U.S. Pat. Nos. 3,937,226, 4,088,140, 4,548,203, 4,458,677, 4,332,259 are summarized in U.S. Pat. Nos. 4,928,688 and 5,674,259, all incorporated herein by reference. The advantages of providing sensing in addition to pacing in both the right and left heart chambers is addressed in U.S. Pat. Nos. 4,928,688 and 5,674,259, as well as in U.S. Pat. Nos. 4,354,497, 5,174,289, 5,267,560, 5,514,161, and 5,584,867, also all incorporated herein by reference.
The medical literature also discloses a number of approaches of providing multi-chamber pacing as set forth in: Daubert et al., “Permanent Dual Atrium Pacing in Major Intra-atrial Conduction Blocks: A Four Years Experience”, PACE (Vol. 16, Part II, NASPE Abstract 141, p. 885, April 1993); Daubert et al., “Permanent Left Ventricular Pacing With Transvenous Leads Inserted Into The Coronary Veins”, PACE (Vol. 21, Part II, pp. 239-245, January 1998); Cazeau et al., “Four Chamber Pacing in Dilated Cardiomyopathy”, PACE (Vol. 17, Part II, pp. 1974-1979, November 1994); and Daubert et al., “Renewal of Permanent Left Atrial Pacing via the Coronary Sinus”, PACE (Vol. 15, Part II, NASPE Abstract 255, p. 572, April 1992), Cazeau et al., PACE (Vol. 17, November 1994, Part II, pp. 1974-1979), all incorporated herein by reference.
In addition to the above-mentioned disclosures concerning the advantages of substantially simultaneous or synchronous pacing of the two ventricles, it is known that there is an advantage to synchronous pacing of the left atrium and the right atrium for patients with IAB. The advantage of synchronous pacing of the two atria for patients with IAB was disclosed at AHA 1991, Abstract from 64th Scientific Sessions, “Simultaneous Dual Atrium Pacing in High Degree Inter-Atrial Blocks: Hemodynamic Results”, Daubert et al., No. 1804. Further, it is known that patients with IAB are susceptible to retrograde activation of the left atrium, with resulting atrial tachycardia. Atrial resynchronization through pacing of the atria can be effective in treating the situation. PACE, Vol. 14, April 1991, Part II, p. 648, “Prevention of Atrial Tachyarrythmias Related to Inter-Atrial Block By Permanent Atrial Resynchronization”, Mabo et al., No. 122. For patients with this condition, a criterion for pacing is to deliver a left atrial stimulus before the natural depolarization arrives in the left atrium.
Since the stimulation of the vagus nerve appears to have the desired effect of simultaneously reducing inflammation by targeting multiple components of the inflammatory cascade, VNS in combination with bi-ventricular pacing may provide an improvement to the current therapies for treating and/or managing the multi-faceted syndromes of chronic heart failure. Therefore, it is desirable to provide methods and systems for controllably stimulating the vagus nerve in combination with multi-site pacing of the heart for treating heart failure.